Tony Schapira on GBA1 Parkinson's disease

So let's please start with, with the basics, and of course, the basics about GBA1.

So what is it? What is GBA1, and why should neurologists be interested in this protein, uh, which I learned is a lysosomal enzyme?

Yes.

So GBA1 is the gene that encodes glucocerebrosidase, uh, for the lysosome, and it's an important enzyme in cellular function, and I'll come back to the importance of lysosomes for neurologists in a moment.

But just to dwell for a, a few minutes on GBA1.

So GBA1, as I say, encodes glucocerebrosidase.

Now, this is an important lysosomal enzyme, but its relevance to medicine really goes back almost 150 years-

Oh, wow

...

when, uh, Philippe Gaucher in France first described a patient, uh, with an enlarged spleen and other bone marrow abnormalities that was thought at that time to be a type of cancer.

But of course, that was 150 years ago.

But the description that he gave to the disease and the combination of symptoms and signs that was later to bear his name, Gaucher disease, was subsequently identified in the 1960s as due to deficiency of glucocerebrosidase.

This is an important lysosomal enzyme.

It is, in terms of Gaucher disease, an autosomal recessive disorder, so biallelic mutations of the GBA1 gene cause Gaucher.

The relevance to neurology in particular is that certain severe mutations of GBA1 can cause what's called neuronopathic Gaucher disease.

These cases are usually seen by pediatricians.

But the relevance to more broad, uh, neurology came with the identification that mutations or variants, as we now know them to be, of GBA1 are significantly associated with Parkinson disease.

And this came about through several observations, uh, predominantly initially from Israel, but subsequently by Ellen Sidransky, who undertook, um, the formal genetic meta-analysis of GBA1, who identified a very strong association of variants with Parkinson disease.

And this was not only those people who had Gaucher disease, but their first-degree relatives who were obligate carriers had a significantly increased risk of developing Parkinson disease.

So that observation clearly associated GBA1 with Parkinson disease, and we now know that variants in GBA1 are the commonest genetic association of Parkinson disease.

In the UK, for instance, about, um, 11% of, uh, Parkinson, uh, patients have GBA1 variants, and this is the same worldwide.

Of course, the percentages vary a little depending on how the work was undertaken, but generally speaking, from 5 to 15% of Parkinson, uh, populations have GBA1 variants.

This can rise to 20 to 25% in the Ashkenazi population.

So it's a very common and very important association with Parkinson disease.

Now, why would neurologists be interested in lysosomes? Well, obviously because of the GBA1 connection, but it's not just GBA1.